Thrombosis and Anticoagulant Therapy PDF

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Summary

Coagulation Regulation and Fibrinolysis- The balance can be tipped in either direction by alteration in physiological or clinical conditions. - Balance is maintained by all the factors involved in fibrinolysis and coagulation.Endothelium Roles- Anticoagulant, endothelium will act as a barrier betwee...

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MLSC-3121U, Clinical Hematology II Coagulation Regulation and Fibrinolysis -

The balance can be tipped in either direction by alteration in physiological or clinical conditions. Balance is maintained by all the factors involved in fibrinolysis and coagulation.

Endothelium Roles -

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Anticoagulant, endothelium will act as a barrier between platelets and collagen to inhibit platelet adhesion in a non-injured state. Done through a continuous release of aggregation inhibitors. Prothrombotic, the endothelium is prothrombotic since platelets will adhere to the subendothelial collagen to become activated and secrete chemicals to signal more platelets for aggregation during injury.

Platelet Roles -

Platelets are attracted to the site of injury to adhere to collagen in response to injury. Platelets also aggregate with fibrinogen to form a platelet plug (primary hemostasis). Aims to stop the bleeding to provide a surface for secondary hemostasis to occur.

Coagulation Factors and Thrombin Generation Roles -

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Thrombin, serves to o Form fibrin from fibrin monomers. o Activates FXIII to FXIIIa. o Activates FV, FVIII and FXI. o Promotes primary hemostasis o Binds thrombomodulin. Antithrombin, inactivates thrombin and acts on FXa, FIXa, FXIa and FXIIa. Heparin will increase the speed of AT’s inhibition of these factors. Heparin Cofactor II, specific thrombin inhibitor. Works against thrombin but not as well as antithrombin does. Protein C and S, activated protein C with cofactor Protein S inactivates FVa and FVIIIa. Tissue Factor Pathway Inhibitor, binds FVIIa/tissue factor inhibiting further activation of FX or FIX via the extrinsic pathway.

Fibrinolysis -

The process of fibrin clot dissolution via plasmin. Plasminogen is the inactivated form of plasmin. Plasminogen Activators, include Tissue Plasminogen Activator (t-PA), urokinase and streptokinase. Plasminogen Inhibitors, include plasminogen activator inhibitor-1.

MLSC-3121U, Clinical Hematology II -

Plasmin Inhibitors, include alpha-2-antiplasmin (primary inhibitor). FDP, the fragments left behind after fibrinolysis. The most clinically significant on is ddimer as it is only produced when plasmin works on fibrin. D-Dimer Test, d-dimer is only produced when plasmin breaks down fibrin clots. The test is used to diagnose thrombosis and is indicated for deep vein thrombosis. The ELISA assay method is the gold standard for this test.

Thrombosis -

Inappropriate of a platelet or fibrin clot that impedes regular blood flow through obstruction of blood vessels. It is the most common cause of death in western countries. Thrombophilia, predisposition to thrombosis secondary to a congenital or acquired disorder.

Hereditary Venous Thrombosis Risk Factors -

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APC resistance, caused by a deficient anticoagulant response of plasma to the addition of APC. Involves the gene defect of FV (Factor V Leiden). Mutated FV cannot be inactivated by APC, causing procoagulant activity to persist. Most common risk factor in Caucasians. o Factor V Leiden, resistant FV remains active and increases thrombin production due to an amino acid substitution in the Factor V gene. Protein C Deficiency, autosomal dominant gene mutation. Can also be acquired in liver disease or warfarin therapy. Protein S Deficiency, autosomal dominant gene mutation. Can also be acquired in liver disease or warfarin therapy. Antithrombin Deficiency, autosomal dominant gene mutation. Can also be acquired through liver disease or heparin therapy. Anti-thrombin activity is enhanced by fractionated and/or unfractionated heparin. Prothrombin Gene Mutation, results in an elevated prothrombin level and activity with increased risk of DVT. Hyperhomocysteinemia, risk factor for development of early atherosclerotic vascular disease and venous thrombosis. Can be acquired through folate deficiency or B12 and/or B6. Other Risk Factors, defects of fibrinolysis system, presence of acquired antiphospholipid antibodies (Lupus anticoagulant, LA), and elevation in FVIII and fibrinogen levels.

Acquired Thrombophilia -

Lupus Anticoagulant/Antiphospholipid Syndrome (LA), LA antibodies lead to a prolonged APTT and involves the inhibition of APC and antithrombin dependant anticoagulant. Also inhibits fibrinolysis.

MLSC-3121U, Clinical Hematology II -

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Heparin Induced Thrombocytopenia, characterized by the sudden unexplained decrease in platelet counts occurring 5 or more days after heparin therapy. Heparin complexes with PF4 and antibodies against it are produced. When bound to a platelet, the spleen recognizes those antibodies and removes it along with the platelets they’ve attached to. o Lab Diagnosis, uses an ELISA antigen assay. Uses a H-PF4 complex as the target antigen to detect HIT immunoglobulin. o Therapy, mainly involves the ceasing/substitution of unfractionated heparin treatment. Diagnosis of thrombosis is mainly built on family history (acquired or congenital) PT, APTT, TT and reptilase are commonly ordered to diagnose thrombophilia. APC-R, PC, PS and AT deficiency are also tested for along with fibrinogen and plasminogen assays. Factor FXII activity is also evaluated.

Disseminated Intravascular Coagulation -

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Consumption of coagulation factors and platelets leading to excessive thrombus formation throughout the microcirculation. Causes of DIC include activation of the extrinsic system (increase tissue thromboplastin) or intrinsic system (with FXIIa formation) and the direct activation of FX or FII. The extrinsic system is activated by the release of tissue thromboplastin, which activates FVII in massive injury, sepsis, obstetrical complications, or tumours. DIC is secondary to an underlying condition. Intrinsic activation can be caused by indirect endothelial cell damage and subendothelial exposure. Direct activation is done by venom, malignancy and acute pancreatitis. Lab results include o Prolonged PT/APTT o Thrombocytopenia o Elevated d-dimer o Soluble fibrin monomers o Fibrin deposition in biopsy material o Fragmented RBCs Therapy, the underlying condition must be treated first to stop the DIC. Blood volume and hemostatic function is maintained afterward. Thrombin Time (TT), measures the time required for thrombin to convert fibrinogen to insoluble fibrin clot. Affected by abnormal levels of fibrinogen, dysfibrinogenemia, presence of circulation anticoagulants such as heparin and FDPs. Reptilase Time, uses the same principle as the TT test but forms a much more fragile clot. Not inhibited by heparin.

MLSC-3121U, Clinical Hematology II

Anticoagulation Therapy -

Prevents the propagation of the thrombus to reduce the risk of an embolus. Allows for natural resolution of thrombosis.

Oral Anticoagulants -

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Coumarin Compound, also known as warfarin. Acts by inhibiting the recycling of vitamin K to slow down vitamin K dependant factors. Treatment is monitored with the PT and INR. INR should be kept between 2.0 and 3.0. Warfarin was discovered in cattle when there was an outbreak caused by spoiled clover being eaten by the cows. The molecule in the spoiled clover, Coumarin, was affecting the cow’s coagulation factors causing the cows to bleed to death when it inhibited their clotting. Warfarin, leads to the production of coagulation factors with reduced anticoagulant functions. Acts on vitamin K dependant factors FII, FVII, FIX and FX. Also acts on Protein C, S and Z (inhibitory proteins also known as proteins induced by vitamin K antagonists (PIVKA)). Prophylaxis, used to prevent strokes in patients with atrial fibrillation and thrombosis after trauma in surgery. Oral anticoagulants are given to people most commonly after they have had a thrombotic event. They are also most likely already on heparin to prevent clotting. The Warfarin works on the vitamin K factors. The patient may stay on both oral anticoagulants and heparin until the patient is at an INR between 2.0 to 3.0. Unfractionated Heparin, a large molecule that functions as a cofactor with antithrombin to accelerate the rate at which AT is capable of binding to thrombin or FXa, inhibiting their activity. Heparin is monitored with the APTT test. The APTT should be 1.5 to 2.5 the upper limit. Heparin can also be monitored directly in the blood using a heparin Xa assay. Heparin Resistance, inflammation causes hyper-fibrinogenemia and increase factor VIII. This shortens the APTT and causes decreased sensitivity to heparin. Platelet poor plasma is required for heparin testing since they release platelet factor 4 which neutralizes heparin. Heparin Overdose, protamine can be administered to neutralize heparin. Low Molecular Weight Heparin (LMWH), has a greater impact on the inhibition of FXa than other enzymes. Given via a subcutaneous injection and does not require monitoring since there is a fixed dose response. Lab Monitoring of LMWH, APTT is insensitive to LMWH and cannot test for LMWH. Instead, anti-Xa chromogenic assays are used. The assay produces a coloured product with an intensity that is inversely proportional to heparin concentration. Alternative Direct Oral Anticoagulants (DOACs), include Hirudin which uses the APTT or new Ecarin clotting time for monitoring.

MLSC-3121U, Clinical Hematology II -

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Ecarin Clotting Time (ECT), uses snake enzymes to convert prothrombin to intermediate meizothrombin which converts fibrinogen to fibrin. DTIs bind meizothrombin in a linear, dose-dependant prolongation of the ECT. Antiplatelet Agents, work on platelets to prevent clotting. Include Aspirin, Clopidogrel, Ticlopidine, Prasugrel and Ticagrelor. Aspirin, it inhibits platelet aggregation to prolong bleeding times. All the other antiplatelet agents work by supressing platelet aggregation and secretion response to adenosine diphosphate. Thrombolytic Therapy, include accelerating clot lysis and using urokinase, streptokinase and tissue plasminogen activator. PT, APTT, fibrinogen, TT and plt count are also monitored. Patient may also be on heparin which could interfere with TT testing. Patients with high hematocrits will raise the anticoagulant to plasma ratio in the collection tube. Results in falsely prolonged clot-based tests....